Insm1 promotes endocrine cell differentiation by modulating the expression of a network of genes that includes Neurog3 and Ripply3.
Insm1 promotes endocrine cell differentiation by modulating the expression of a network of genes that includes Neurog3 and Ripply3.
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DOI：
10.1242/dev.104810
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发表时间：
2014-08
期刊：
影响因子：
--
通讯作者：
Magnuson MA
中科院分区：
文献类型：
--
作者：
Osipovich AB;Long Q;Manduchi E;Gangula R;Hipkens SB;Schneider J;Okubo T;Stoeckert CJ Jr;Takada S;Magnuson MA
胰岛素瘤相关基因1(Insm1)在中枢神经系统、外周神经系统、嗅觉上皮和内分泌胰腺的细胞发育中起着重要的调节作用。为了更好地确定Insm1在胰腺内分泌细胞发育中的作用，我们产生了带有Insm1GFPCre报告等位基因的小鼠，并用它们来研究Insm1表达和缺失群体。缺乏Insm1的内分泌祖细胞分化较低，在激素产生、细胞增殖和细胞迁移方面存在广泛的缺陷。缺乏Insm1的胚胎含有更多的非编码Neurog3mRNA剪接变体，并且有更少的Neurog3/Insm1共表达的祖细胞，这表明Insm1正向调节Neurog3。此外，表达高水平或低水平Pdx1的内分泌祖细胞，因此可能偏向于形成特定的细胞系，在Insm1调控的基因中表现出细胞类型的特异性差异。对Ripply3的功能分析表明，Ripply3对早期内分泌细胞的增殖具有负面调节作用。综上所述，这些发现表明，在发育中的胰腺内分泌细胞中，Insm1通过抑制前体细胞程序和激活RNA剪接、细胞迁移、受控细胞增殖、血管生成、细胞外基质和激素分泌所必需的基因，促进从导管前体细胞向坚定的内分泌细胞的转变。
Insulinoma associated 1 (Insm1) plays an important role in regulating the development of cells in the central and peripheral nervous systems, olfactory epithelium and endocrine pancreas. To better define the role of Insm1 in pancreatic endocrine cell development we generated mice with an Insm1GFPCre reporter allele and used them to study Insm1-expressing and null populations. Endocrine progenitor cells lacking Insm1 were less differentiated and exhibited broad defects in hormone production, cell proliferation and cell migration. Embryos lacking Insm1 contained greater amounts of a non-coding Neurog3 mRNA splice variant and had fewer Neurog3/Insm1 co-expressing progenitor cells, suggesting that Insm1 positively regulates Neurog3. Moreover, endocrine progenitor cells that express either high or low levels of Pdx1, and thus may be biased towards the formation of specific cell lineages, exhibited cell type-specific differences in the genes regulated by Insm1. Analysis of the function of Ripply3, an Insm1-regulated gene enriched in the Pdx1-high cell population, revealed that it negatively regulates the proliferation of early endocrine cells. Taken together, these findings indicate that in developing pancreatic endocrine cells Insm1 promotes the transition from a ductal progenitor to a committed endocrine cell by repressing a progenitor cell program and activating genes essential for RNA splicing, cell migration, controlled cellular proliferation, vasculogenesis, extracellular matrix and hormone secretion.
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